The broad, long-term goal of this application is to discover and develop pharmacotherapies for the treatment of substance abuse. Specifically, we will develop potent and selective kappa opioid receptor antagonists to treat opiate addicts in withdrawal, including relapse to the opiates. Selective kappa opioid antagonists may also be useful in preventing relapse to cocaine addiction. Potent and selective delta opioid receptor antagonists have potential as pharmacotherapies to prevent relapse to opiates, cocaine, and alcohol abuse. Importantly, compounds developed will also serve as biochemical and pharmacological probes useful in gaining a better understanding of the biochemical and molecular mechanisms of opiate, cocaine, and alcohol addiction. Significant research findings directed toward the specific aims of the current grant were achieved. We discovered JDTic and (-)-KAA1 as potent and selective K opioid receptor antagonists and (+)-KF4 as a potent and selective d opioid receptor antagonist that is also an inverse agonist. All three compounds are small molecules that will penetrate the CNS and have high stability. Thus, all three are highly useful lead structures for the development of pharmacotherapies for treating substance abuse. The unique pharmacological properties of JDTic have already led to its selection for preclinical development. This application is for continuing support of the present program. The proposed research continues to be based on the original hypothesis that pharmacotherapies for treating substance abuse can be discovered and developed through lead optimization of novel compounds from the opioid research area. The scope of the proposed studies will involve: (1) design and synthesis of novel lead structures based on the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine, 4beta-and 9beta-methyl-5-(3-hydroxyphenyl)morphan, and 4a-(3-hydroxyphenyl)-8a-methyldecahydroisoquinoline classes of opioid antagonists; (2) in vitro evaluation of compounds using radioligand binding and [35S]GTPgammaS functional assays; and (3) in vivo evaluation of potent kappa and delta selective antagonists discovered for their effects on kappa and delta agonist-induced diuresis and antinociception in rat models. Selected compounds will be submitted to the NIDA Opioid Treatment Discovery Program (OTDP) for evaluation in a mouse antinociceptive assay, foot shock-induced reinstatement of responding for heroin and cocaine in rat models, and morphine-induced physically dependent rat model. Compounds that are potent delta selective opioid receptor inverse agonists will be evaluated by Dr. Chris Evans (UCLA) in a chronic antinociception rat model.